B. van Zaane

Incidence of Venous Thromboembolism in Patients with Cushing's Syndrome: A Multicenter Cohort Study

CONTEXT Venous thrombosis has frequently been reported in patients with endogenous Cushings syndrome (CS). OBJECTIVE The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. DESIGN AND SETTING We conducted a multicenter cohort study at all university medical centers in The Netherlands. PATIENTS Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. MAIN OUTCOME MEASURES We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. RESULTS A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). CONCLUSIONS Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.

Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors.

Summary.  Background: Whether glucocorticoid use contributes to a hypercoagulable state, and thereby enhances the thrombotic risk, is controversial. Objective: We aimed to examine the effects of glucocorticoid use on coagulation and fibrinolysis. Methods: MEDLINE and EMBASE databases were searched to identify published studies comparing glucocorticoid treatment with a glucocorticoid‐free control situation. Subjects could be either patients or healthy volunteers. Two investigators independently performed study selection and data extraction. Results were expressed as standardized mean difference, if possible; data were pooled with a random‐effects model. Results: Of the 1967 identified publications, 36 papers were included. In healthy volunteers, a clear rise in factor (F)VII, VIII and XI activity was observed after glucocorticoid treatment, but these data alone provided insufficient evidence to support hypercoagulability. However, during active inflammation, glucocorticoids significantly increased levels of plasminogen activator inhibitor‐1 (PAI‐1), whereas levels of von Willebrand factor (VWF) and fibrinogen decreased. Peri‐operative use of glucocorticoids inhibited the increase in tissue‐type plasminogen activator induced by surgery. Conclusions: The present study showed differential effects of glucocorticoids depending on the clinical situation in which it is given, most likely as a result of their disease modifying properties. Clinical outcome studies are needed to adequately assess the risk‐benefit of glucocorticoid use per population when thrombotic complication is the focus.

The effect of hyperthyroidism on procoagulant, anticoagulant and fibrinolytic factors

Several coagulation and fibrinolytic parameters appear to be affected by thyroid hormone excess; however, the net effect on the haemostatic system remains unclear. We aimed to update our previous review and systematically summarise and meta-analyse the data by assessing the effects of thyrotoxicosis on the coagulation and fibrinolytic system in vivo . Data sources included MEDLINE (2006-2012), EMBASE (2006-2012), and reference lists. The sources were combined with our previous search containing studies from 1980-2006. Eligible studies were all observational or experimental studies. Two investigators independently extracted data and rated study quality. Weighted mean proportion and 95% confidence intervals were calculated and pooled using a fixed and a random-effects model. A total of 29 articles consisting of 51 studies were included, as in several articles more than one study was described. We included four intervention (before and after treatment in hyperthyroid patients), five cross-sectional (hyperthyroid subjects and euthyroid controls), and four experimental (before and after use of thyroid hormone in euthyroid subjects) medium/high quality studies for meta-analysis. We found that thyrotoxicosis shifts the haemostatic balance towards a hypercoagulable and hypofibrinolytic state with a rise in factors VIII and IX, fibrinogen, von Willebrand factor, and plasminogen activator inhibitor-1. This was observed in endogenous and exogenous thyrotoxicosis, and in subclinical as well as overt hyperthyroidism. We conclude that both subclinical and overt hyperthyroidism induce a prothrombotic state, which is therefore likely to be a risk factor for venous thrombosis.

Hypothyroidism and acquired von Willebrand’s syndrome: a systematic review

Summary.  Acquired von Willebrand’s syndrome type I is the supposed main underlying cause of bleeding tendency in hypothyroid patients. The purpose of this systematic review was to summarize the published evidence on the association between hypothyroidism and acquired von Willebrand’s syndrome. All published clinical epidemiological and interventional studies, case reports and in vitro studies that investigated the association between hypothyroidism and acquired von Willebrand’s syndrome were identified by a computer‐assisted search of the MEDLINE and EMBASE electronic databases. A quality assessment was performed for clinical epidemiological studies. A total of 41 papers were included. A total of 22 epidemiological in vivo studies, two in vitro studies and 47 case reports were finally analyzed. No high quality in vivo study was identified. Almost all bleeding episodes described in the case reports were mucocutaneous. von Willebrand factor (VWF) antigen value was available for 23 patients: median value 28 U/dL (range: 4–45); VWF activity was available for 24 patients: median value 28.5 U/dL (range: <3–55); factor VIII activity was available for 16 patients: median value 47 U/dL (range: 9–74). Acquired von Willebrand’s syndrome may be the main factor responsible for bleeding diathesis in overt hypothyroid patients. Even if bleeding episodes are mainly mild and mucocutaneous, blood transfusion, drug administration or surgical procedure may be required.

Thyroid Dysfunction and Fibrin Network Structure: A Mechanism for Increased Thrombotic Risk in Hyperthyroid Individuals

CONTEXT Hyperthyroidism is associated with increased thrombosis risk, and fibrin clot structure determines susceptibility to vascular thrombotic events. OBJECTIVE Our objective was to investigate clot formation and lysis in hyperthyroidism using observational and interventional studies. DESIGN Ex vivo fibrin clot structure/fibrinolysis and plasma levels of thrombotic/inflammatory markers were investigated in hyperthyroid individuals (n = 24) and matched controls (n = 19), using turbidimetric assays, ELISA, and confocal and electron microscopy. The effects of normalizing thyroid function were analyzed (n = 19) and the role of short-term exogenous hyperthyroidism in healthy volunteers studied (n = 16). RESULTS Hyperthyroid subjects displayed higher clot maximum absorbance compared with controls (0.41 ± 0.03 and 0.27 ± 0.01 arbitrary units, respectively; P < 0.01), and longer clot lysis time (518 ± 23 and 461 ± 18 sec, respectively; P < 0.05), which correlated with free T(4) levels. Plasma levels of fibrinogen and plasminogen activator inhibitor-1 were significantly higher in patients compared with controls. Normalizing thyroid function in 19 subjects was associated with lower maximum absorbance and shorter lysis time, accompanied by reduction in fibrinogen, plasminogen activator inhibitor-1, and D-dimer levels. Complement C3, but not C-reactive protein, levels were higher in hyperthyroid subjects compared with controls (0.92 ± 0.05 and 0.64 ± 0.03 g/liter, respectively; P < 0.01), correlated with clot structure parameters, and decreased after intervention. Confocal and electron microscopy confirmed more compact clots and impaired fibrinolysis during hyperthyroidism. Exogenous hyperthyroidism in healthy volunteers had no effect on any of the clot structure parameters. CONCLUSIONS Endogenous hyperthyroidism is associated with more compact clots and resistance to fibrinolysis ex vivo, related to the degree of hyperthyroidism and C3 plasma levels, and these changes are modulated by achieving euthyroidism. Altered clot structure/lysis may be one mechanism for increased thrombotic risk in hyperthyroidism.

Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study.

Summary.  Background: Several hemostatic abnormalities have been reported in hyperthyroidism, but the overall effect of thyroid hormone excess on coagulation and fibrinolysis is unclear. Objective: Our aim was to assess whether the use of supraphysiological doses of levothyroxine leads to coagulation activation and inhibition of fibrinolysis. Patients and methods: Healthy volunteers were randomized to receive levothyroxine or no medication for 14 days with a washout period of at least 28 days in a crossover design. To study the effects of different degrees of thyroid hormone excess, 16 participants received levothyroxine in a dose of 0.3 mg per day, and 12 received levothyroxine 0.45 or 0.6 mg per day depending on body weight. Several variables of coagulation and fibrinolysis were measured. Results: Levels of von Willebrand factor activity (VWF:RiCo) and antigen (VWF:Ag), factor (F) VIII, plasminogen activator inhibitor‐1 (PAI‐1) and clot‐lysis time were slightly higher after levothyroxine 0.3 mg per day than after the control situation, but only levels of VWF showed a significant increase from baseline. After levothyroxine 0.45 or 0.6 mg per day, levels of fibrinogen increased by 17%, VWF activity by 24%, VWF antigen by 26%, FVIII by 19%, FIX by 14%, FX by 7%, PAI‐1 by 116% and clot‐lysis time by 14%, and activated partial thromboplastin time decreased by 3%; all were significant changes compared with the control situation. We did not observe clear evidence of coagulation activation. Conclusions: Our data suggest that thyroid hormone excess increases coagulation factor levels and inhibits fibrinolysis in a dose‐dependent fashion. This implies an increased risk of venous thrombosis during hyperthyroidism.

The effect of changes in thyroxine and thyroid-stimulating hormone levels on the coagulation system.

Introduction: Thyroid dysfunction is known to affect levels of factor VIII, von Willebrand factor and fibrinogen. Although altered coagulation parameters are related to levels of thyroid hormone, this is possibly partially mediated by thyroid stimulating hormone (TSH). Our aim was to examine the effect of TSH and free thyroxine (FT4) on coagulation factors, with a focus on factor VIII (FVIII), von Willebrand factor (VWF) and fibrinogen. Methods: In patients successfully treated for well-differentiated thyroid carcinoma, either levothyroxine was withdrawn for 4 weeks (n=11) or recombinant TSH was administered (n=17) to stimulate thyroglobulin production. We measured levels of FVIII, VWF and fibrinogen, besides prothrombin, factor VII, factor IX, antithrombin, protein C and S, prothrombin fragment 1+2 and thrombin-antithrombin complex on two different occasions. Results: In patients who changed from hypothyroidism to a slightly hyperthyroid state, a rise in FVIII (+39.1 U/dL), VWF (+32.0 U/dL), and fibrinogen (+0.6 g/L) was found. In patients in whom stable FT4 levels accompanied rising levels of TSH, no effect on coagulation parameters was observed. Conclusions: The results of our study suggest that increasing levels of free thyroxine are associated with a rise in FVIII, VWF, and fibrinogen levels. This shift is not mediated by TSH. Introduction Thyroid dysfunction is known to affect the coagulation system. In patients with overt hypothyroidism, an increased bleeding time, prolonged prothrombin time and activated partial thromboplastin time, as well as decreased levels of factor VIII (FVIII), fibrinogen and von Willebrand factor (VWF) have been observed, occasionally leading to a bleeding tendency, similar to acquired von Willebrand’s disease. After adequate suppletion with levothyroxine, these coagulation factors return to normal levels. In hyperthyroidism, elevated levels of VWF and fibrinogen have consistently been observed. These changes in coagulation parameters may have clinical implications, such as an increased risk of venous thrombosis in hyperthyroidism. Although the altered coagulation parameters are related to levels of thyroid hormone, it is possible that the effect on coagulation is either completely or partially mediated by thyroid stimulating hormone (TSH, or thyrotropin). We set out to examine and disentangle the effect of changes in TSH and serum free thyroxine (FT4) levels on FVIII, VWF and fibrinogen, which are the coagulation factors for which an effect of thyroid hormones is best documented. In addition, we studied other coagulation factors to explore whether they were influenced by FT4 and TSH levels. We had the opportunity to study the separate effects of these hormones in two series of patients successfully treated for well-differentiated thyroid carcinoma. For follow-up, serum thyroglobulin (TG) level is used as a tumour marker. To assess serum thyroglobulin levels in a maximally stimulated condition, high levels of TSH are induced. This can be achieved either by withdrawal of levothyroxine for several weeks, or by the administration of recombinant human TSH (rhTSH) while continuing levothyroxine treatment. Measuring coagulation factors at different stages in both TG stimulating protocols can provide clues whether changes in levels of FT4 or TSH affect the coagulation system. Materials and Methods Study population Patients successfully treated for differentiated thyroid carcinoma by surgery and radioactive iodine ablation of the residual thyroid gland were derived from a larger study on the influence of thyroid hormone on metabolism and gene expression in relation to heart rate and blood pressure. Prior to a TSH-stimulated diagnostic protocol, consisting of either thyroxine withdrawal or recombinant TSH injection, patients from the Department of Endocrinology of the Leiden University Medical Centre, Leiden, the Netherlands (a tertiary referral centre for differentiated thyroid carcinoma) were asked to participate in the study. In all patients, successful treatment was defined as the absence of measurable serum TG levels during TSH stimulation and negative total-body scintigraphy. Patients with a haemoglobin level below 7.1 mmol/L, recent blood donation, diabetes mellitus, a body mass index above 35 kg/m, pregnancy, or other endocrine disorders, as well as postmenopausal women were excluded, in addition to patients using any drugs known to influence coagulation. In total, 12 patients undergoing thyroxine withdrawal and 17 patients receiving rhTSH were eligible for the present analysis.

High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis: the MEGA study

Thyroid hormone affects the coagulation system, but its effect on clinical disease is not clear. We determined the associations of levels of free thyroxine (FT4), thyroid‐stimulating hormone (TSH) and anti‐thyroid peroxidase antibodies (antiTPO) with levels of coagulation factors and the risk of venous thrombosis.

Acquired von Willebrand syndrome in patients with overt hypothyroidism: a prospective cohort study

Numerous case reports have been published on acquired von Willebrand syndrome (aVWS) in patients with hypothyroidism, but no prospective studies have been published. The aim of this study was to investigate laboratory and clinical characteristics of aVWS in patients with newly diagnosed overt hypothyroidism. An observational cohort study was performed between May 2007 and February 2012. Consecutive hypothyroid patients before or within the first 48 h of replacement therapy were enrolled. At inclusion, blood was sampled for coagulation tests and bleeding history was documented by means of a standardized bleeding questionnaire. Repeat samples were obtained after restoration of euthyroidism. The prevalence of aVWS, defined as von Willebrand factor antigen (VWF:Ag) ≤50% and/or VWF ristocetin activity (VWF:RCo) ≤50%, was calculated. Patients with aVWS were subsequently divided into severe (VWF:Ag and/or VWF:RCo ≤10%), moderate (VWF:Ag and/or VWF:RCo between 10 and 30%) or mild (VWF:Ag and/or VWF:RCo between 30 and 50%). A total of 90 patients were included among whom a prevalence of aVWS of 33% was found. There were no patients with severe aVWS. Eight patients (9%) had moderate aVWS and 21 (23%) had mild aVWS. Bleeding score was negatively correlated with both VWF:Ag (β −0.32, P = 0.03) and VWF:RCo (β −0.32, P = 0.02). After restoration of euthyroidism, VWF:Ag had significantly increased by 44%, VWF:RCo by 36%, factor VIII by 39%, and endogenous thrombin potential by 10%. aVWS has a high prevalence in hypothyroid patients. Highest bleeding scores in patients with lower VWF levels suggest clinical relevance.

Thrombin-activatable fibrinolysis inhibitor in hypothyroidism and hyperthyroxinaemia

Endocrine disorders affect both the coagulation and fibrinolytic systems, and have been associated with the development of cardiovascular diseases. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a link between coagulation and the fibrinolytic system. The aim of this study was to determine the effect of thyroid hormone excess and deficiency on TAFI levels and function. The effect of hyperthyroxinemia on TAFI was studied in healthy volunteers who were randomised to receive levothyroxine or no medication for 14 days in a crossover design. The effect of hypothyroidism on TAFI was studied in a multicentre observational cohort study. Blood was drawn before treatment of patients with newly diagnosed hypothyroidism and when euthyroidism was achieved. Plasma clot-lysis times, activated TAFI (TAFIa)-dependent prolongation of clot-lysis and TAFI levels were measured. Thyroid hormone excess resulted in a hypofibrinolytic condition and in an enhanced TAFIa-dependent prolongation of clot lysis. A trend towards decreased plasma TAFI levels was observed in healthy volunteers who used levothyroxine. Hypothyroidism resulted in hyperfibrinolysis and a reduced TAFIa-dependent prolongation of clot lysis. In conclusion, alterations of TAFIa-dependent prolongation of clot lysis in patients with thyroid disorders may cause an impaired haemostatic balance. The disturbed haemostatic balance in patients with hyperthyroidism might make them prone to thrombosis, while the risk for bleeding may increase in patients with hypothyroidism.